The overall objective of this proposal is to develop a fundamental understanding of the role of localized transport regions (LTRs) in low-frequency sonophoresis (LFS), with an emphasis on: 1. Understanding if the LTRs are Indeed Regions of Highly-Localized Transdermal Transport for both Hydrophilic and Hydrophobic Permeants: Specifically, demonstrating whether the LTRs are regions of high permeability compared to the surrounding regions of ultrasound-treated skin (the non-LTRs) for a broad class of permeants. 2. Understanding the Mechanisms that Govern the Formation of the LTRs in LFS: Specifically, understand: i) the role of the surfactant sodium lauryl sulfate (SLS) in LTR formation, and ii) the roles of acoustic cavitation, the ultrasound acoustic field, and the skin surface topography in LTR formation. 3. Understanding the Nature of the Permeation Pathways that Exist within the LTRs and the Non-LTRs: Specifically, identify the type of permeation pathway (transcellular, intercellular, or a combination of both) followed by permeant molecules traversing the skin within the LTRs and the non-LTRs. 4. Investigating the Safety of LTR Formation on Skin Treated with LFS: Specifically, determining: i) the reversibility of LTR formation in the skin, and ii) the biological effects of LTR formation. 5. Mathematical Modeling of Transdermal Transport in the Presence of LTRs: Specifically, i) developing mathematical models to more accurately evaluate experimental transdermal permeabilities across ultrasound-treated skin with LTRs, and ii) developing models to confirm the presence of transcellular and/or intercellular transdermal pathways within the LTRs and the non-LTRs in the stratum corneum resulting from the ultrasound treatment.